The antiviral (HIV, HBV) properties of the unnatural L-nucleoside analogs e.g. Dioxolane-T, 3TC, FTC, as well as their remarkably low cytotoxicities, are well established. Unfortunately, the rapid onset of high-level HIV drug resistance associated with the L-enantiomers (but not with the more cytotoxic D-family) nullifies the effectiveness of these drugs. Ring- expanded 1,3-dihetero nucleoside analogs, athe higher homologs of the 'unnatural' compounds, incorporate structural features of potential importance in the design of new antiviral agents. The synthesis of these compounds will be undertaken and their biological properties investigated. Appropriate placement of heteroatoms (O,S) can provide conformational control and allow-access to 6-membered nucleosides possessing axial heterobases. Resembling natural beta-nucleosides, this conformation is favorable for kinase-mediated 5'-phosphorylation. Achiral cis-1,3-dihetero nucleosides should be a non--cytotoxic due to lack of recognition by host cell enzymes. But, like their lower homologs, they may well be potent RT inhibitors. Furthermore, their symmetry properties suggest a structure- based method to avoid the rapid drug resistance associated with the l- family. To examine these possibilities and to provide new structure-activity correlations, three series of nucleosides will be synthesized; 1,3- dioxanes, 1,3-dithianes, and 1,3-oxathianes. The compounds will be obtained starting from glycerol or 3-mercapto-1,2-propanediol, utilizing Mitsunobu-type alkylation. Asymmetric synthesis will used in athe 1,3- oxathiane series. Configurations and conformations will be established by NMR techniques. The compounds will be collaboratively screened for activity against HIV, herpes and HBV and, if warranted, for drug resistance.